Penicillins and cephalosporins are .beta.-lactam antibiotics which are widely used in medicine. There is continued interest, however, in obtaining new .beta.-lactam variants to better combat strains of microorganisms that acquire resistance to antibiotics inculding commonly used penicillins and cephalosporins. Very recently new antibiotics, such as cephamycins and nocardicins have been discovered which are also .beta.-lactam derivatives.
The last few years have seen great progress toward economically promising total synthesis of penicillins, cephalosporins and analogs and the key step in this process consists in reacting an .alpha.-azidoacyl chloride with an imino compound in the presence of a teritary amine to form an .alpha.-azido-.beta.-lactam which may be monocyclic or polycyclic depending on the imino compound.
Bose and co-workers devised this synthetic method and effected the total synthesis of 6-epipenicillin and various penam and cephem derivatives (A. K. Bose, G. Spiegelman and M. S. Manhas, J. AM. Chem. Soc., 90, 4506 (1968)). The .alpha.-azido-.beta.-lactam in each case obtained from an appropriate imino compound is reduced to an .alpha.-amino-.beta.-lactam and modified in various ways to provide, .alpha.-amido-.beta.-lactams (cis or trans), .alpha.-alkoxy-.beta.-lactams, etc.
The .alpha.-azido-.beta.-lactam approach has been used by several research groups for the total synthesis of various penicillins, cephalosporins, carba and oxa analogs of cephalosporins, isocephalosporin and its oxa-analogs, nocardicins, etc. (B. G. Christensen and R. W. Ratcliffe, Annual Reviews of Medicinal Chemistry, Chap. 28, 271 (1976)).
Although successful in the laboratory for the synthesis of a wide variety of monocyclic and polycyclic .beta.-lactams, the .alpha.-azido-.beta.-lactam method suffers from serious disadvantages for large scale production of .alpha.-amino-.beta.-lactam compounds. Azidoacetic acid and azidoacetyl chloride have been reported to be prone to violent decomposition, especially during purification by distillation under reduced pressure of the latter and this purification is important for obtaining satisfactory .beta.-lactam formation. The reduction of .alpha.-azido-.beta.-lactam to .alpha.-amino-.beta.-lactam is also a step that requires careful control to ensure a high yield of the desired product. Unexpected .beta.-lactam cleavage reactions have been reported by Bose et al (J. Org. Chem., Vol. 38, (1973), p. 1238) during the catalytic reduction and subsequent acylation of .alpha.-azido-.beta.-lactams. Therefore, it is desirable--in particular for large scale production--to develop an alternative approach to the synthesis of .alpha.-amino-.beta.-lactams. The present invention consitutes such an approach.
Various protective groups have been devised in peptide chemistry to provide temporary protection to the amino group of an amino acid while the carboxy group of the same molecule is activated and utilized for amide bond formation. One such protective group described by Dane et al (Agnew Chem. Int. Ed. Vol. 1 (1962), p. 658) appeared to be of potential value to a synthesis of this type. In this method, an amino acid such as valine, alanine or phenyl-alanine is reacted with an 1,3-diketone or a .beta.-ketoester in the presence of alkali to form a vinylamino acid salt (A), for example according to the following reaction scheme: ##STR5## wherein R, R.sub.1 and R.sub.2 are selected organic radicals or hydrogen atoms.
The vinylamino acid salt (A) can be reacted with a chloroformate ester and an amino acid ester to form a protected dipeptide ester (C). Mild acid treatment of (C) removes the protective group to to provide a dipeptide ester (D): ##STR6## wherein R.sub.3 is as defined above for R-R.sub.2 and R' and R.sub.4 are ester radicals.
Some of the diketones and .beta.-ketoesters that are commonly used in the above method are shown in Table I.
TABLE I ______________________________________ ##STR7## R.sub.1 R.sub.2 ______________________________________ 1 CH.sub.3 OCH.sub.3 2 CH.sub.3 OC.sub.2 H.sub.5 3 CH.sub.3 OC(CH.sub.3).sub.3 4 CH.sub.3 CH.sub.3 5 C.sub.6 H.sub.5 CH.sub.3 ______________________________________
Others are depicted in the following formulae: ##STR8##
I attempted to react vinylamino acid salts of type (A) prepared from amino acids such as alanine, valine, phenylalanine, etc. with imino compounds such as benzalaniline via the mixed anhydride route but met with failure in obtaining any .beta.-lactam.
Vinylamino ketones are known to be reactive and capable of undergoing various types of condensation reaction. Thus, a recent report (S. Auricchio, R. Bernardi and A. Ricca, Tetrahedron Letters; 4831-4834 (1976)) describes the formation of a substituted aniline as well as a pyridine derivative from 4-ethylamino-3-penten-2-one.
The reaction of vinylamino acid salts with alkyl chloroformates has been reported to produce 1,3-oxazolidin-5-ones in high yield (S. K. Gupta, Synthesis, 724 (1975)).
Vinylamino acid salts have been shown to react with trifluoracetic anhydride to give pyrrole compounds (S. K. Gupta, Synthesis, 726 (1975)).
In the light of the foregoing, it is fully unexpected that in the process of the present invention certain vinylamino salts of glycine can be reacted under selected conditions with certain imino compounds to form monocyclic and polycyclic .beta.-lactams.